Murph
Senior Member (Voting Rights)
IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis
Peng Zhang 1 , Junlai Liu 1 , Allen Lee 1 , Irene Tsaur 1 , Masafumi Ohira 1 , Vivian Duong 1 , Nicholas Vo 1 , Kosuke Watari 1 , Hua Su 1 , Ju Youn Kim 1 , Li Gu 1 , Mandy Zhu 1 , Shabnam Shalapour 2 , Mojgan Hosseini 3 , Gautam Bandyopadhyay 4 , Suling Zeng 5 , Cristina Llorente 5 , Haoqi Nina Zhao 6 , Santosh Lamichhane 7 , Siddharth Mohan 6 , Pieter C Dorrestein 6 , Jerrold M Olefsky 4 , Bernd Schnabl 5 , Pejman Soroosh 8 , Michael Karin 9
Affiliations
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs.
MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes.
This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance.
Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.
Peng Zhang 1 , Junlai Liu 1 , Allen Lee 1 , Irene Tsaur 1 , Masafumi Ohira 1 , Vivian Duong 1 , Nicholas Vo 1 , Kosuke Watari 1 , Hua Su 1 , Ju Youn Kim 1 , Li Gu 1 , Mandy Zhu 1 , Shabnam Shalapour 2 , Mojgan Hosseini 3 , Gautam Bandyopadhyay 4 , Suling Zeng 5 , Cristina Llorente 5 , Haoqi Nina Zhao 6 , Santosh Lamichhane 7 , Siddharth Mohan 6 , Pieter C Dorrestein 6 , Jerrold M Olefsky 4 , Bernd Schnabl 5 , Pejman Soroosh 8 , Michael Karin 9
Affiliations
- PMID: 39317186
- DOI: 10.1016/j.cmet.2024.08.012
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs.
MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes.
This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance.
Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.